Plasma and urinary concentrations of methamphetamine after oral administration of famprofazone to man

1. To obtain further evidence for the metabolic formation of methamphetamine from famprofazone in man, concentrations of methamphetamine in plasma, as well as in urine, were measured by g.l.c. In addition, intact famprofazone and famprofazone N-oxide were analysed in the urine.

2. Methamphetamine appeared in plasma 1 h after a single 100mg dose of the drug to two male subjects, and the concentration maintained between 24 and 44ng/ml over 2-12 h, declining to 10ng/ml and an undetectable level respectively after 24 h.

3. Total urinary excretion of methamphetamine over 72 h was 1·9mg for a 25 mg dose and 2·2mg for a 50mg dose. After a 100mg dose, 4·6 mg of methamphetamine was excreted over 36h. Neither intact famprofazone nor famprofazone N-oxide were detected when the urine samples after the 100mg dose were examined.

4. The results provide further evidence that methamphetamine is a bona fide human metabolite of famprofazone and suggest that at least 20% dose may be broken down via the pathways leading to the formation of methamphetamine. This could have significant clinical implications as the result of pharmacological activity of this metabolite.     

Plasma concentrations and haemodynamic effects of d-sotalol after beta-blockade in dogs

This study was designed to investigate the haemodynamic effects of d-sotalol at plasma concentrations producing class III antiarrhythmic effects. d-Sotalol 1, 4 and 10 mg/kg intravenously was given after beta-blockade (propranolol 0.25 mg/kg intravenously) to seven pentobarbital anaesthetized dogs. Left ventricular (LV) systolic and end-diastolic pressures, LV dP/dtmax, mean aortic pressure, stroke volume, cardiac output and total peripheral resistance were not significantly changed by d-sotalol. There was a linear correlation between the dose of d-sotalol infused and the plasma concentration of d-sotalol obtained. Heart rate decreased and QT-time increased with increasing plasma concentrations of d-sotalol, whereas the QRS-width did not change. There was a linear correlation between the decrease in heart rate and the increase in QT-time, and between the plasma concentration of d-sotalol and increase in QT-time. In conclusion, the study indicates that after beta-blockade, d-sotalol has no cardiodepressive effects at concentrations that prolong repolarization.     

Plasma and urinary concentrations of methamphetamine after oral administration of famprofazone to man.

1. To obtain further evidence for the metabolic formation of methamphetamine from famprofazone in man, concentrations of methamphetamine in plasma, as well as in urine, were measured by g.l.c. In addition, intact famprofazone and famprofazone N-oxide were analysed in the urine. 2. Methamphetamine appeared in plasma 1 h after a single 100 mg dose of the drug to two male subjects, and the concentration maintained between 24 and 44 ng/ml over 2-12 h, declining to 10 ng/ml and an undetectable level respectively after 24 h. 3. Total urinary excretion of methamphetamine over 72 h was 1.9 mg for a 25 mg dose and 2.2 mg for a 50 mg dose. After a 100 mg dose, 4.6 mg of methamphetamine was excreted over 36 h. Neither intact famprofazone nor famprofazone N-oxide were detected when the urine samples after the 100 mg dose were examined. 4. The results provide further evidence that methamphetamine is a bona fide human metabolite of famprofazone and suggest that at least 20% dose may be broken down via the pathways leading to the formation of methamphetamine. This could have significant clinical implications as the result of pharmacological activity of this metabolite.     

Plasma metronidazole concentrations after single and repeated vaginal pessary administration.

Metronidazole concentrations in plasma were measured by h.p.l.c. in 12 healthy female volunteers after single and repeated vaginal administration of 500 mg metronidazole pessaries. The area under the plasma concentration-time curve (AUC(0,12 h) was 8.4 +/- 3.9 micrograms ml-1 h (mean +/- s.d.) on day 1 and 20.6 +/- 7.1 micrograms ml-1 h (mean +/- s.d.) on day 5. The peak plasma drug concentration on day 1 was 1.2 +/- 0.6 micrograms ml-1 (mean +/- s.d.) and on day 5 it was 2.0 +/- 0.7 micrograms ml-1 (mean +/- s.d.). The plasma concentration of metronidazole at steady state was above the minimum inhibitory concentration (MIC) for anaerobic Streptococci and Clostridium tetani. These results demonstrate much lower systemic exposure than after oral administration.     

Plasma concentrations of megestrol acetate and medroxyprogesterone acetate after single oral administration to healthy subjects

Plasma concentrations of megestrol acetate (MA) were measured by radioimmunoassay (RIA) after a single oral dose of 60 mg either in the form of one tablet, or four 15 mg tablets, to 10 women 21-40 years old using a cross-over design. No statistically significant difference between the two preparations was observed with respect to plasma concentrations, the area under the curve from 0 to 24 h or the maximum concentration (c(max)). For comparison, data are presented on the plasma level of medroxyprogesterone acetate (MPA) following a single oral dose of 100 mg given using a cross-over design in two different tablet forms to 10 healthy men, when no significant difference was observed for these parameters. The mean c(max) for MA after 2.6 h was 43.9 ng/ml (range 21.7-87.7 ng/ml), whereas that for MPA at 3.1 h was 13.1 ng/ml (range 4.4-29.5 ng/ml) despite the higher dose. After 24 h immunoreactive MA and MPA ranged from 9.6 to 29.0 ng/ml and from 0.2 to 4.0 ng/ml respectively. Moreover, it was found that petroleum ether extraction gives the most specific result by RIA, although considerable amounts of metabolites are still co-estimated. By comparison with selected ion monitoring using GC-MS, metabolite interference in RIA increases with time after administration of the steroids and is considerably greater for MPA than for MA. It is concluded that after oral administration the relative bioavailability of MA is significantly better than that of MPA.     

Plasma and cerebrospinal fluid concentrations of indomethacin in children after intravenous administration

The objective of this study was to evaluate the cerebrospinal fluid (CSF) permeation of indomethacin in healthy children. The participants (n = 31, aged 4-144 months) received indomethacin (0.35 mg/kg) as a 10-minute intravenous infusion prior to surgery under spinal anaesthesia. A single CSF and plasma sample from each individual was collected 14 to 225 minutes after the infusion. Indomethacin concentrations were determined from the CSF, plasma, and protein-free plasma. Total plasma, protein-free plasma, and CSF concentrations of indomethacin ranged between 90 and 2200 ng/mL (median, 780 ng/mL), 0.3 and 0.8 ng/mL (median, 0.5 ng/mL), and 0.2 and 5.0 ng/mL (median, 1.4 ng/mL), respectively. The CSF to plasma concentration ratio remained less than 0.01. There was no correlation between the administration time and CSF concentrations. Eleven children developed 12 nonserious adverse effects, from which 5 were central nervous system (CNS) effects (agitation). In conclusion, indomethacin permeated into the CSF of children, which enables both desired and adverse CNS effects of indomethacin.     

Plasma naltrexone kinetics after intravenous bolus administration in dogs and monkeys.

This investigation generated data characterize a specific electron-capture GLC assay reported previously for naltrexone and applied the method to a determination of naltrexone pharmacokinetics. Extraction efficiencies are reported for the assay, and mass spectral evidence indicates that naltrexone forms a triester when derivatized for electron-capture GLC with pentafluoropropionic anhydride and a base catalyst. Plasma level-time data for intravenous naltrexone at two dose levels in monkeys yielded no evidence of dose-dependent kinetics. A two-compartment open pharmacokinetic model was fitted to plasma level-time data for naltrexone in two dogs and yielded a total body clearance of 51-55 ml/min/kg. Urine collected for 0-24 hr contained 36% of the dose as naltrexone conjugates with less than 1% as unchanged naltrexone. Plasma level-time data for intravenous naltrexone in six monkeys yielded an average terminal half-life of 7.8 hr and a total body clearance of 64 ml/min/kg. The total body clearance for naltrexone was greater than the hepatic plasma or blood flow in both dogs and monkeys. This finding, together with the extremely low renal excretion of naltrexone, suggests the existence of elimination mechanisms besides liver metabolism and renal excretion.     

Quantitation of propoxyphene and its major metabolites in heroin addict plasma after large dose administration of propoxyphene napsylate.

A sensitive and specific GLC assay method was developed for the determination of propoxyphene, its major metabolite norpropoxyphene, and lesser known metabolites cyclic dinorpropoxyphene and/or dinorpropoxyphene in plasma of heroin addicts administered up to 800 mg of propoxyphene napsylate. The assay used a mass internal standard of pyrroliphene. The compounds were extracted from pH 9.8 carbonate-buffered plasma with butyl chloride, back-extracted into acidified water which was then washed with hexane, and reextracted with chloroform from the aqueous phase made basic. Quantitation of the drug and its metabolites was accomplished by temperature-programmed GLC. Absolute identification of the compounds chromatographed was completed by GLC-mass spectrometry.     

Plasma concentrations of isosorbide dinitrate after oral administration of a sustained-release formulation to human subjects

1. A peak of mean plasma concentrations of isosorbide dinitrate of 5.8 ng/ml was reached at 0.5 h after a single oral dose of 5 mg in a standard tablet formulation. Thereafter mean concentrations declined with a half-life of about 48 min. 2. A peak of mean concentrations of isosorbide dinitrate of 3.2 ng/ml was reached at 2--4 h after a single oral dose of 20mg in a sustained-realease capsule formulation (Iso Mack Retard). Thereafter mean concentrations declined by about twofold during 6 h and were still detectable at 12 h after dosing. 3. When corrected by dose/bodyweight variations, the mean area under the isosorbide dinitrate plasma concentration curve from the sustained-release capule was 76% of that from the standard tablet and this formulation-related difference in bioavailability was statistically significant (p less than 0.05). 4. The results showed that sustained-release formulation is a useful way to maintain plasma concentrations of isosorbide dinitrate for several hours.     

Plasma and urine aluminium concentrations in healthy subjects after administration of sucralfate.

1. Sucralfate (basic sucrose aluminium sulphate), a topical intestinal agent, was administered in suspension or granule form to 25 healthy subjects at a total dose of 4 g day-1 for 21 days. Aluminium in plasma and 24 h urine samples was assayed before, during and after administration of sucralfate by inductively coupled plasma optical emission spectrometry. 2. Sucralfate produced significant increases in plasma and urine aluminium concentrations. On average, plasma aluminium increased from about 2 micrograms 1-1 to more than 5 micrograms 1-1 and 24 h urine aluminium increased from less than 5 micrograms to more than 30 micrograms. Both plasma and urine aluminium concentrations decreased rapidly after sucralfate was stopped. However, urinary aluminium concentrations remained higher than normal 5 and 10 days after discontinuation of sucralfate administration. Moreover subjects receiving sucralfate granules had significantly higher average urinary excretion of aluminium than subjects receiving the suspension. 3. The small but significant increase in plasma and urine aluminium following sucralfate administration in therapeutic doses may reflect intestinal absorption of aluminium. Although such absorption would appear to be moderate in healthy subjects, it is suggested that aluminium-based treatments should be used only intermittently, especially in patients with renal disorders.     

Plasma and CSF morphine concentrations after i.m. and epidural administration

Morphine concentrations in plasma and CSF after i.m. and epidural morphine administration were assayed in patients undergoing surgery of the low abdomen. Morphine concentration in CSF after i.m. administration of this drug is remarkably lower than morphine concentration in plasma. The highest value is attained in CSF after about 90' and is followed by a slow downsloping to lowest values, which were observed 4 hours after drug administration. Kinetics of morphine passage into plasma after epidural administration is similar to that found after i.m. administration. In the latter experimental condition (epidural administration), concentrations of morphine in CSF 30' after administration are markedly lower than those found in plasma. However, 60 min. after epidural administration plasma and CSF morphine concentrations are similar, in particular CSF concentrations are 4 to 8 times higher than those obtained after i.m. administration. Such high levels persist for a long time.     

Propoxyphene and norpropoxyphene tissue concentrations in fatalities associated with propoxyphene hydrochloride and propoxyphene napsylate

Propoxyphene and its major metabolite norpropoxyphene have been determined in blood and liver in 29 cases of death in which propoxyphene, either as the hydrochloride or as the napsylate salt, was involved. The use of propoxyphene napsylate (Darvon-N) contributed to the deaths of 4 persons, 3 of whom were former heroin addicts receiving large amounts of this drug in connection with propoxyphene substitution programs. In the majority of cases the norpropoxyphene blood concentrations exceed the propoxyphene concentrations, although brain determinations in several instances indicate that norpropoxyphene does not cross the blood-brain barrier with the same ease as propoxyphene. On the basis of the comparative toxicities of propoxyphene and norpropoxyphene in animals and the high tissue concentrations of norpropoxyphene in man after propoxyphene administration, it is conceivable that norpropoxyphene contributes to the toxic effects of propoxyphene.     

Plasma concentrations of isosorbide dinitrate after administration of increasing doses of a sustained-release formulation to human subjects

Plasma concentrations of isosorbide dinitrate have been measured after administration of increasing doses in the range 20--100 mg as sustained-release tablets (Isoket retard) containing 20 mg to human subjects. Means of peak concentrations of 4.2 ng/ml, 13.1 ng/ml, 20.7 ng/ml, 36.8 ng/ml, and 34.9 ng/ml were measured after doses of 20 mg, 40 mg, 60 mg, 80 mg and 100 mg, respectively. In the plasma of individual subjects, peak concentrations of isosorbide dinitrate increased in proportion to the dose administered. Areas under the plasma isosorbide dinitrate concentration-time curves also increased in proportion to the dose administered. Bioavailability parameters were better correlated to the dose over the range 20--60 mg than over the range 20--100 mg.     

Plasma mexiletine concentrations following combined oral and intramuscular administration

Summary Mexiletine in doses of 50, 100 and 400 mg was administered by intramuscular injection to a healthy subject and the resulting plasma concentrations were compared with those after 100 mg given intravenously. The bioavailability of mexiletine given by this route is complete and the kinetics are linear with dose. Plasma mexiletine concentrations resulting from 200 mg given orally with either two 4-ml intramuscular injections each containing 100 mg (Mexitil_® — for intravenous use) or one 2-ml intramuscular injection of an experimental preparation containing 200 mg were compared in 3 and 6 normal subjects respectively. Plasma levels within the therapeutic range of 0.75–2 µg/ml were attained at mean times of 28.7 and 42.5 min respectively. Apart from raised plasma creatine phosphokinase levels (as would be expected following an intramuscular injection) the tolerability of intramuscular mexiletine injections was satisfactory. Further studies in patients will be required to determine whether the combined oral and intramuscular administration of mexiletine is of value in acute myocardial infarction.